Showing papers by "University of Newcastle published in 2014"

Biological insights from 108 schizophrenia-associated genetic loci

Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Reaching the hard-to-reach: a systematic review of strategies for improving health and medical research with socially disadvantaged groups

Abstract: Background This study aims to review the literature regarding the barriers to sampling, recruitment, participation, and retention of members of socioeconomically disadvantaged groups in health research and strategies for increasing the amount of health research conducted with socially disadvantaged groups.

Sucrose metabolism: gateway to diverse carbon use and sugar signaling.

Abstract: Sucrose metabolism plays pivotal roles in development, stress response, and yield formation, mainly by generating a range of sugars as metabolites to fuel growth and synthesize essential compounds (including protein, cellulose, and starch) and as signals to regulate expression of microRNAs, transcription factors, and other genes and for crosstalk with hormonal, oxidative, and defense signaling. This review aims to capture the most exciting developments in this area by evaluating (a) the roles of key sucrose metabolic enzymes in development, abiotic stress responses, and plant–microbe interactions; (b) the coupling between sucrose metabolism and sugar signaling from extra- to intracellular spaces; (c) the different mechanisms by which sucrose metabolic enzymes could perform their signaling roles; and (d ) progress on engineering sugar metabolism and transport for high yield and disease resistance. Finally, the review outlines future directions for research on sugar metabolism and signaling to better understand and improve plant performance.

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

Abstract: A multidisciplinary panel of 18 physicians and 3 nonphysicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Partial Least Squares Structural Equation Modeling (PLS-SEM): A Useful Tool for Family Business Researchers

Abstract: Structural equation modeling (SEM) has become a mainstream method in many fields of business research, but its use in family business research remains in its infancy. This lag in SEM’s application holds especially true for partial least squares SEM (PLS-SEM), an alternative to covariance-based SEM, which provides researchers with more flexibility in terms of data requirements, model complexity and relationship specification. This article draws attention to PLS-SEM as an opportunity to advance the development and testing of theory in family business research by providing a non-technical introduction into the basic concepts and issues of PLS-SEM, bearing the needs of potential users in mind. To this end, a systematic procedure for PLS-SEM results evaluation is presented and applied to an annotated example. The article also illustrates the analysis of mediating effects, which researchers are increasingly testing in their models.

The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation

Abstract: Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1β (IL-1β) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1β. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1β in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication.

Formula versus donor breast milk for feeding preterm or low birth weight infants

Abstract: BACKGROUND: When sufficient maternal breast milk is not available, alternative forms of enteral nutrition for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula. Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants. However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants. OBJECTIVES: To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight (LBW) infants. SEARCH METHODS: We used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5), Ovid MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (3 May 2019), as well as conference proceedings, previous reviews, and clinical trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses. We assessed the certainty of evidence for the main comparison at the outcome level using GRADE methods. MAIN RESULTS: Twelve trials with a total of 1879 infants fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and eight compared nutrient-enriched preterm formula versus donor breast milk. Only the five most recent trials used nutrient-fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials. Most of the included trials were funded by companies that made the study formula.Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). These meta-analyses contained high levels of heterogeneity. We did not find evidence of an effect on long-term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.05; number needed to treat for an additional harmful outcome (NNTH) 33, 95% CI 20 to 100; 9 studies, 1675 infants).The GRADE certainty of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotising enterocolitis (downgraded for imprecision). AUTHORS' CONCLUSIONS: In preterm and LBW infants, moderate-certainty evidence indicates that feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.

The Health Benefits of Muscular Fitness for Children and Adolescents: A Systematic Review and Meta-Analysis

Abstract: Physical fitness during childhood and adolescence has been identified as an important determinant of current and future health status. While research has traditionally focused on the association between cardio-respiratory fitness and health outcomes, the association between muscular fitness (MF) and health status has recently received increased attention. The aim of this systematic review and meta-analysis was to evaluate the potential physiological and psychological benefits associated with MF among children and adolescents. A systematic search of six electronic databases (PubMed, SPORTDiscus, Scopus, EMBASE, PsycINFO and OVID MEDLINE) was performed on the 20th May, 2013. Cross-sectional, longitudinal and experimental studies that quantitatively examined the association between MF and potential health benefits among children and adolescents were included. The search yielded 110 eligible studies, encompassing six health outcomes (i.e., adiposity, bone health, cardiovascular disease [CVD] and metabolic risk factors, musculoskeletal pain, psychological health and cognitive ability). The percentage of studies reporting statistically significant associations between MF and the outcome of interest was used to determine the strength of the evidence for an association and additional coding was conducted to account for risk of bias. Meta-analyses were also performed to determine the pooled effect size if there were at least three studies providing standardised coefficients. Strong evidence was found for an inverse association between MF and total and central adiposity, and CVD and metabolic risk factors. The pooled effect size for the relationship between MF and adiposity was r = −0.25 (95 % CI −0.41 to −0.08). Strong evidence was also found for a positive association between MF and bone health and self-esteem. The pooled effect size for the relationship between MF and perceived sports competence was r = 0.39 (95 % CI 0.34–0.45). The evidence for an association between MF and musculoskeletal pain and cognitive ability was inconsistent/uncertain. Where evidence of an association was found, the associations were generally low to moderate. The findings of this review highlight the importance of developing MF in youth for a number of health-related benefits.

Evolutionary algorithms and other metaheuristics in water resources

Abstract: The development and application of evolutionary algorithms (EAs) and other metaheuristics for the optimisation of water resources systems has been an active research field for over two decades. Research to date has emphasized algorithmic improvements and individual applications in specific areas (e.g. model calibration, water distribution systems, groundwater management, river-basin planning and management, etc.). However, there has been limited synthesis between shared problem traits, common EA challenges, and needed advances across major applications. This paper clarifies the current status and future research directions for better solving key water resources problems using EAs. Advances in understanding fitness landscape properties and their effects on algorithm performance are critical. Future EA-based applications to real-world problems require a fundamental shift of focus towards improving problem formulations, understanding general theoretic frameworks for problem decompositions, major advances in EA computational efficiency, and most importantly aiding real decision-making in complex, uncertain application contexts.

Modelagem de Equações Estruturais com Utilização do Smartpls

Abstract: The objective of this article is to present a didactic example of Structural Equation Modeling using the software SmartPLS 20 M3 The program mentioned uses the method of Partial Least Squares and seeks to address the following situations frequently observed in marketing research: Absence of symmetric distributions of variables measured by a theory still in its beginning phase or with little “consolidation”, formative models, and/or a limited amount of data The growing use of SmartPLS has demonstrated its robustness and the applicability of the model in the areas that are being studied

Electric-field control of magnetic order above room temperature

Abstract: Electric-field-induced switching of material’s magnetization is a promising approach for achieving energy-efficient memory devices. By taking advantage of the strong magnetoelectric coupling with a BaTiO3 substrate, a small electric field is used to switch a FeRh thin film from anti- to ferromagnetic above room temperature.

Identifying miRNAs, targets and functions

Abstract: microRNAs (miRNAs) are small endogenous non-coding RNAs that function as the universal specificity factors in post-transcriptional gene silencing. Discovering miRNAs, identifying their targets and further inferring miRNA functions have been a critical strategy for understanding normal biological processes of miRNAs and their roles in the development of disease. In this review, we focus on computational methods of inferring miRNA functions, including miRNA functional annotation and inferring miRNA regulatory modules, by integrating heterogeneous data sources. We also briefly introduce the research in miRNA discovery and miRNA-target identification with an emphasis on the challenges to computational biology.

Electric Vehicle Battery Charging/Swap Stations in Distribution Systems: Comparison Study and Optimal Planning

Abstract: Electric vehicle (EV) is a promising technology for reducing environmental impacts of road transport. In this paper, a framework for optimal design of battery charging/swap stations in distribution systems based on life cycle cost (LCC) is presented. The battery charging/swap station models are developed to compare the impacts of rapid-charging stations and battery swap stations. Meanwhile, in order to meet the requirements of increased power provided during the charging period, the distribution network should be reinforced. In order to control this reinforcement cost, stations should be placed at appropriate places and be scaled correctly. For optimal cost-benefit analysis and safety operation, the LCC criterion is used to assess the project and a modified differential evolution algorithm is adopted to solve the problem. The proposed method has been verified on the modified IEEE 15-bus and 43-bus radial distribution systems. The results show that battery swap station is more suitable for public transportation in distribution systems.

Multistep Finite Control Set Model Predictive Control for Power Electronics

Abstract: For direct model predictive control with reference tracking of the converter current, we derive an efficient optimization algorithm that allows us to solve the control problem for very long prediction horizons. This is achieved by adapting sphere decoding principles to the underlying optimization problem. The proposed algorithm requires only few computations and directly provides the optimal switch positions. Since the computational burden of our algorithm is effectively independent of the number of converter output levels, the concept is particularly suitable for multi-level topologies with a large number of voltage levels. Our method is illustrated for the case of a variable speed drive system with a three-level voltage source converter.

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Abstract: The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Physical activity and physical self-concept in youth: systematic review and meta-analysis.

Abstract: Evidence suggests that physical self-concept is associated with physical activity in children and adolescents, but no systematic review of this literature has been conducted. The primary aim of this systematic review and meta-analysis was to determine the strength of associations between physical activity and physical self-concept (general and sub-domains) in children and adolescents. The secondary aim was to examine potential moderators of the association between physical activity and physical self-concept. A systematic search of six electronic databases (MEDLINE, CINAHL, SPORTDiscus, ERIC, Web of Science and Scopus) with no date restrictions was conducted. Random effects meta-analyses with correction for measurement were employed. The associations between physical activity and general physical self-concept and sub-domains were explored. A risk of bias assessment was conducted by two reviewers. The search identified 64 studies to be included in the meta-analysis. Thirty-three studies addressed multiple outcomes of general physical self-concept: 28 studies examined general physical self-concept, 59 examined perceived competence, 25 examined perceived fitness, and 55 examined perceived appearance. Perceived competence was most strongly associated with physical activity (r = 0.30, 95 % CI 0.24–0.35, p < 0.001), followed by perceived fitness (r = 0.26, 95 % CI 0.20–0.32, p < 0.001), general physical self-concept (r = 0.25, 95 % CI 0.16–0.34, p < 0.001) and perceived physical appearance (r = 0.12, 95 % CI 0.08–0.16, p < 0.001). Sex was a significant moderator for general physical self-concept (p < 0.05), and age was a significant moderator for perceived appearance (p ≤ 0.01) and perceived competence (p < 0.05). No significant moderators were found for perceived fitness. Overall, a significant association has been consistently demonstrated between physical activity and physical self-concept and its various sub-domains in children and adolescents. Age and sex are key moderators of the association between physical activity and physical self-concept.

Distributed Formation Control of Multi-Agent Systems Using Complex Laplacian

Abstract: The paper concentrates on the fundamental coordination problem that requires a network of agents to achieve a specific but arbitrary formation shape. A new technique based on complex Laplacian is introduced to address the problems of which formation shapes specified by inter-agent relative positions can be formed and how they can be achieved with distributed control ensuring global stability. Concerning the first question, we show that all similar formations subject to only shape constraints are those that lie in the null space of a complex Laplacian satisfying certain rank condition and that a formation shape can be realized almost surely if and only if the graph modeling the inter-agent specification of the formation shape is 2-rooted. Concerning the second question, a distributed and linear control law is developed based on the complex Laplacian specifying the target formation shape, and provable existence conditions of stabilizing gains to assign the eigenvalues of the closed-loop system at desired locations are given. Moreover, we show how the formation shape control law is extended to achieve a rigid formation if a subset of knowledgable agents knowing the desired formation size scales the formation while the rest agents do not need to re-design and change their control laws.

Exploring positively- versus negatively-valenced brand engagement: a conceptual model

Abstract: Purpose – After gaining traction in business practice the “brand engagement” (BE) concept has transpired in the academic marketing/branding literature. BE has been defined as the level of a consumer's “cognitive, emotional and behavioral investment in specific brand interactions”. Although pioneering research provides exploratory insights, the majority of literature to-date addresses consumers' specific positively-valenced BE; thus largely overlooking potential negatively-valenced manifestations of this emerging concept and their ensuing implications. The purpose of this paper is to propose a novel BE conceptualization that extends to cover focal negatively-valenced, in addition to positively-valenced BE expressions, thus providing a more comprehensive theoretical model of BE. Specifically, while positively-valenced BE addresses consumers' favorable/affirmative cognitive, emotional and behavioral brand-related dynamics during focal brand interactions (e.g. brand-usage); negatively-valenced BE, by contrast...

The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing.

Abstract: Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.

A Systematic Review of Cybersickness

Abstract: The uptake of new interface technologies, such as the Oculus Rift have generated renewed interest in virtual reality especially for private entertainment use. However, long standing issues with unwanted side effects, such as nausea from cybersickness, continue to impact on the general use of devices such as head mounted displays. This in turn has slowed the uptake of more immersive interfaces for computer gaming and indeed more serious applications in training and health. In this paper we report a systematic review in the area of cybersickness with a focus on measuring the diverse symptoms experienced. Indeed the related conditions of simulator sickness and motion sickness have previously been well studied and yet many of the issues are unresolved. Here we report on these issues along with a number of measures, both subjective and objective in nature, using either questionnaires or psychophysiological measures that have been used to study cybersickness. We also report on the factors, individual, device related and task dependent that impact on the condition. We conclude that there remains a need to develop more cost-effective and objective physiological measures of both the impact of cybersickness and a person's susceptibility to the condition.

Social cognitive theory and physical activity: a systematic review and meta‐analysis

Abstract: Summary This review investigated three research questions (i) What is the utility of social cognitive theory (SCT) to explain physical activity (PA)?; (ii) Is the effectiveness of SCT moderated by sample or methodological characteristics? and (iii) What is the frequency of significant associations between the core SCT constructs and PA? Ten electronic databases were searched with no date or sample restrictions. Forty-four studies were retrieved containing 55 SCT models of PA. Methodological quality was assessed using a standardized tool. A random-effects meta-analysis revealed that SCT accounted for 31% of the variance in PA. However, methodological quality was mostly poor for these models. Methodological quality and sample age moderated the PA effect size, with increases in both associated with greater variance explained. Although self-efficacy and goals were consistently associated with PA, outcome expectations and socio-structural factors were not. This review determined that SCT is a useful framework to explain PA behaviour. Higher quality models explained more PA variance, but overall methodological quality was poor. As such, high-quality studies examining the utility of SCT to explain PA are warranted.

Perceived barriers to smoking cessation in selected vulnerable groups: a systematic review of the qualitative and quantitative literature

Abstract: Objectives To identify barriers that are common and unique to six selected vulnerable groups: low socioeconomic status; Indigenous; mental illness and substance abuse; homeless; prisoners; and at-risk youth. Design A systematic review was carried out to identify the perceived barriers to smoking cessation within six vulnerable groups. Data sources MEDLINE, EMBASE, CINAHL and PsycInfo were searched using keywords and MeSH terms from each database9s inception published prior to March 2014. Study selection Studies that provided either qualitative or quantitative (ie, longitudinal, cross-sectional or cohort surveys) descriptions of self-reported perceived barriers to quitting smoking in one of the six aforementioned vulnerable groups were included. Data extraction Two authors independently assessed studies for inclusion and extracted data. Results 65 eligible papers were identified: 24 with low socioeconomic groups, 16 with Indigenous groups, 18 involving people with a mental illness, 3 with homeless groups, 2 involving prisoners and 1 involving at-risk youth. One study identified was carried out with participants who were homeless and addicted to alcohol and/or other drugs. Barriers common to all vulnerable groups included: smoking for stress management, lack of support from health and other service providers, and the high prevalence and acceptability of smoking in vulnerable communities. Unique barriers were identified for people with a mental illness (eg, maintenance of mental health), Indigenous groups (eg, cultural and historical norms), prisoners (eg, living conditions), people who are homeless (eg, competing priorities) and at-risk youth (eg, high accessibility of tobacco). Conclusions Vulnerable groups experience common barriers to smoking cessation, in addition to barriers that are unique to specific vulnerable groups. Individual-level, community-level and social network-level interventions are priority areas for future smoking cessation interventions within vulnerable groups. Trial registration number: A protocol for this review has been registered with PROSPERO International Prospective Register of Systematic Reviews (Identifier: CRD42013005761).

Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

Abstract: BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.